HT-2157 (also called SNAP 37889 or SNEC-2) is an indolone-derived compound (1,3-dihydro-1-phenyl-3[[3-trifluoromethyl)phenyl]imino]-2H-indol-2-one) having the following structure:

In laboratory studies, HT-2157 has been found to be a highly potent and selective antagonist of the Galanin 3 receptor (GalR3). See, e.g., Swanson et al., Proc. Natl. Acad. Sci. USA, 102, 17489-1494, 2005. GalR3 is one of three G-protein-coupled receptors—the other two being GalR1 and GalR2—that bind the peptide galanin. By inhibiting adenylate cyclase, galanin binding to GalR3 can reduce cAMP levels—a decrease that can be antagonized by HT-2157. See, e.g., Kolakowski et al., J. Neurochem. 71, 2239-2251, 1998.
Galanin is a neurotransmitter involved in a variety of peripheral and central physiological and pathophysiological processes, including gastrointestinal motility, cardiovascular contraction, neuroendocrine function, feeding behavior, pain perception, learning, memory, anxiety, and depression. For a review, see Mitsukawa et al., EXS 102, 7-23, 2010. The three galanin receptors are distributed in numerous areas of the CNS, including those associated with mood, memory, emotion, and pain. Consistent with these observations, studies of HT-2157 in cellular and animal models have shown multiple effects of this compound on function and pathology of the nervous system:
WO 09/086,532 relates to the use of neurite outgrowth assays as a general screen for compounds, including HT-2157, which can enhance and improve memory function.
US 2008/003946 relates to the administration of GalR3 antagonists to modulate neurite outgrowth. Such antagonists include HT-2157 and the E/Z isomers or mixtures thereof. The antagonists can be administered in single or divided doses or in sustained release forms, depending on numerous factors, including the particular symptoms and effect desired.
U.S. 2004/0110821 and WO 04014376 each relate to pyrimidine and indolone derivatives (including HT-2157) that are selective antagonists for the GAL3 receptor. Each describes a method of treating an affective disorder with compositions that can include a pharmaceutically acceptable carrier and a therapeutically effective amount of the selective antagonist. The composition may be in solid form and include lubricants, glidants, and binders.
U.S. 2005/0192337 relates to processes for preparing the HT-2157 compound.
WO 10/009,453 relates to methods and systems of evaluating, identifying, or assessing the effectiveness of memory agents and training protocols in subjects, including macaques and humans. The memory agents can be formulated as a solution, suspension, emulsion, or lyophilized powder, in association with a pharmaceutically acceptable parenteral vehicle.
U.S. 2007/0135509 and U.S. 2007/0135510 each relate to treating cognitive impairments with several different categories of compounds, including HT-2157. Solid forms of compositions suitable for oral administration include pills, capsules, granules, tablets, and powders.
US 2004/0102507 relates to methods for treating depressive and anxiety disorders with indolone compounds, including HT-2157. It further relates to pharmaceutical compositions, including solid forms or liquid forms, which combine such antagonists with a pharmaceutically acceptable carrier.
WO 04/014307 relates to GalR3 antagonists in the treatment of neuropathic pain and cognitive disorders. Such antagonists comprise indolines, including HT-2157. Solid carriers for use with such antagonists can include endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, and compression aids
U.S. Pat. No. 7,642,281 relates to methods for treating cognitive impairments with various compounds, including the indolone compound HT-2157. The indolone compounds can be formulated as capsules, including powder-filled hard gel capsules, as well as suppositories, creams, inhalants, or transdermal patches.
WO 04/014855 relates to crystalline and amorphous forms of HT-2157 and processes for their preparation. It is further directed to pharmaceutical compositions, including those comprising HT-2157, which are useful in treating depression, anxiety, and other CNS disorders. Solid carriers for use in such compositions include endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents.
WO 04/014854 and U.S. 2004/0082615 each relate to treating depression or anxiety with various categories of compounds, including the indolone compound HT-2157. Corresponding pharmaceutical compositions can include HT-2157, along with solid carriers, such as endogenous carriers, encapsulating materials, and powder mixtures.
Ash et al. (Regul. Pept. 166, 59-67, 2010) relates to behavioral studies in rats treated with HT-2157 (SNAP 37889) to evaluate a possible association between galanin and alcohol. Such studies included tests for anxiety and operant self-administration of ethanol.
Konkel et al. (J. Med. Chem. 49, 3757-3758, 2006) relates to a series of 3-imino-2-indolines as high-affinity antagonists of the galanin GAL3 receptor. The antagonists, which include HT-2157, showed high selectivity for GalR3 over a broad panel of targets, including GAL1 and GAL2.
Oegren et al. (CNS Drugs 20, 633-654, 2006) relates generally to the pathophysiology of mood disorders, including the observation that GalR3 receptor antagonists, such as HT-2157, can cross the blood-brain barrier after systemic administration and show antidepressant-like activity in several animal models.
Swanson et al. (Proc. Natl. Acad. Sci. USA 102, 17489-17494, 2005) relates to the use of behavioral, neurochemical, and electrophysiological approaches to investigate anxiolytic- and antidepressant-like effects following acute administration of GalR3-selective antagonists, including HT-2157 (SNAP 37889).
In summary, numerous studies have uncovered a role of GalR3 in modulating function and dysfunction in the nervous system, and they have uniformly disclosed and relied upon the HT-2157 compound itself or conventional HT-2157 formulations. As disclosed in the instant application, however, such conventional formulations have proven unsuitable for therapeutic use in humans, giving rise to significant and previously unreported safety issues. The present application discloses alternative HT-2157 compositions, which utilize an enteric coating, that overcome these safety issues.